CN102973509A - Preparation technology of anthracyclines lipidosome injecta - Google Patents
Preparation technology of anthracyclines lipidosome injecta Download PDFInfo
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- 238000005516 engineering process Methods 0.000 title claims abstract description 27
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- 229940045799 anthracyclines and related substance Drugs 0.000 title abstract 3
- 238000000034 method Methods 0.000 claims abstract description 39
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 24
- 230000008569 process Effects 0.000 claims abstract description 16
- 238000001914 filtration Methods 0.000 claims abstract description 10
- 239000000203 mixture Substances 0.000 claims abstract description 10
- 239000002502 liposome Substances 0.000 claims description 100
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims description 24
- 239000012528 membrane Substances 0.000 claims description 24
- 239000003814 drug Substances 0.000 claims description 23
- 239000002245 particle Substances 0.000 claims description 22
- 239000000243 solution Substances 0.000 claims description 21
- 229940079593 drug Drugs 0.000 claims description 18
- 230000002572 peristaltic effect Effects 0.000 claims description 16
- 239000012071 phase Substances 0.000 claims description 15
- 238000002347 injection Methods 0.000 claims description 13
- 239000007924 injection Substances 0.000 claims description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- 235000012000 cholesterol Nutrition 0.000 claims description 12
- 239000007788 liquid Substances 0.000 claims description 12
- 239000000047 product Substances 0.000 claims description 11
- 150000001454 anthracenes Chemical class 0.000 claims description 10
- 239000012530 fluid Substances 0.000 claims description 9
- 150000003904 phospholipids Chemical class 0.000 claims description 9
- 239000008346 aqueous phase Substances 0.000 claims description 8
- 238000011118 depth filtration Methods 0.000 claims description 6
- 239000008187 granular material Substances 0.000 claims description 6
- 238000012856 packing Methods 0.000 claims description 6
- 239000003643 water by type Substances 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 4
- 230000009471 action Effects 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 4
- 238000004321 preservation Methods 0.000 claims description 4
- 239000008215 water for injection Substances 0.000 claims description 4
- 239000012467 final product Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 27
- 238000001125 extrusion Methods 0.000 abstract description 6
- 230000001954 sterilising effect Effects 0.000 abstract description 4
- 238000004659 sterilization and disinfection Methods 0.000 abstract description 4
- 150000002632 lipids Chemical class 0.000 abstract description 2
- 238000001471 micro-filtration Methods 0.000 abstract description 2
- 239000002808 molecular sieve Substances 0.000 abstract description 2
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 abstract description 2
- 230000000903 blocking effect Effects 0.000 abstract 2
- 238000009776 industrial production Methods 0.000 abstract 2
- 230000001668 ameliorated effect Effects 0.000 abstract 1
- 238000004500 asepsis Methods 0.000 abstract 1
- 238000007781 pre-processing Methods 0.000 abstract 1
- 238000007493 shaping process Methods 0.000 abstract 1
- 229940090044 injection Drugs 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 239000010408 film Substances 0.000 description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 7
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- NAALWFYYHHJEFQ-ZASNTINBSA-N (2s,5r,6r)-6-[[(2r)-2-[[6-[4-[bis(2-hydroxyethyl)sulfamoyl]phenyl]-2-oxo-1h-pyridine-3-carbonyl]amino]-2-(4-hydroxyphenyl)acetyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound N([C@@H](C(=O)N[C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C=1C=CC(O)=CC=1)C(=O)C(C(N1)=O)=CC=C1C1=CC=C(S(=O)(=O)N(CCO)CCO)C=C1 NAALWFYYHHJEFQ-ZASNTINBSA-N 0.000 description 5
- 229960003109 daunorubicin hydrochloride Drugs 0.000 description 5
- DKGAVHZHDRPRBM-UHFFFAOYSA-N tertiry butyl alcohol Natural products CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 239000006185 dispersion Substances 0.000 description 4
- 238000009826 distribution Methods 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 238000011031 large-scale manufacturing process Methods 0.000 description 4
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 description 4
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 3
- 229910052921 ammonium sulfate Inorganic materials 0.000 description 3
- 235000011130 ammonium sulphate Nutrition 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 2
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 2
- 208000001613 Gambling Diseases 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- MWWSFMDVAYGXBV-RUELKSSGSA-N Doxorubicin hydrochloride Chemical compound Cl.O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 MWWSFMDVAYGXBV-RUELKSSGSA-N 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000010924 continuous production Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 229960004679 doxorubicin Drugs 0.000 description 1
- 229960002918 doxorubicin hydrochloride Drugs 0.000 description 1
- 229940035863 doxorubicin liposome injection Drugs 0.000 description 1
- 238000000265 homogenisation Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000000149 penetrating effect Effects 0.000 description 1
- 238000001338 self-assembly Methods 0.000 description 1
- YNQYZBDRJZVSJE-UHFFFAOYSA-M sodium;2,3-dihydroxypropyl 2,3-di(octadecanoyloxy)propyl phosphate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC(=O)OCC(COP([O-])(=O)OCC(O)CO)OC(=O)CCCCCCCCCCCCCCCCC YNQYZBDRJZVSJE-UHFFFAOYSA-M 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- -1 tert-butyl alcohols Chemical class 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000010409 thin film Substances 0.000 description 1
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- Medicinal Preparation (AREA)
Abstract
The invention discloses preparation technology of anthracyclines lipidosome injecta, and adopts miniflow focusing technology, tangential flow technology and molecular sieve lipidosome preparation technology to lower the production cost of lipidosome and expand the production scale of the lipidosome so as to achieve the continuity and automation of the production process. Ethanol is adopted as dissolvent of lipid mixtures, and is high in safety factor and suitable for industrial production. An ameliorated circulation extrusion device is adopted, and thus the extrusion process is continuous, transparent rate is improved, film blocking phenomenon is avoided, production cost is lowered and production efficiency is improved. The miniflow focusing technology is adopted to achieve single-step shaping, and thus the production process is continuous, man-made interference is reduced, asepsis is beneficially guaranteed, and the preparation technology of the anthracyclines lipidosome injecta is easy to operation and suitable for industrial production. Tangential flow microfiltration preprocessing and vertical filtration sterilization are adopted, and thus the film blocking phenomenon is avoided, and the production process is continuous and large-scale.
Description
Technical field
The invention provides a kind of preparation technology of anthracene nucleus medicinal liposome injection, belong to medical technical field.
Background technology
Liposome is the vesicles that phospholipid molecule is dispersed in the similar membrane structure of aqueous phase self assembly formation, and particle diameter arrives several microns in tens nanometers, nineteen sixty-five, found first by Bangham, and be named as subsequently liposome.
The limitation of Liposomal formulation production is mainly manifested in: the conventional preparation method of (1) liposome is comparatively loaded down with trivial details, production technology is difficult for amplifying, cost is high, the repeatability of producing and serialization (2) the aseptic process cost that is difficult to be protected is higher, because the particle size distribution heterogeneity of liposome, and the distinctive structure limitation of filter membrane causes the gambling film phenomenon frequent occurrence of in-depth filtration degerming, more than all be the common difficult problem that is difficult to overcome that the present whole world faces.The patent CN101897667A of Zhongqi Pharmaceutical Technology (Shijiazhuang) Co. Ltd. of Shiyao Group, the preparation technology of its disclosed lipidosome injection is: hydrogenated soy phosphatidyl choline, cholesterol and MPEG-DSPE are dissolved in ethanol/tert-butyl alcohol aqueous solution, organic solvent is removed in lyophilizing, with the ammonium sulfate aquation, put in order with microjet again, obtain liposome turbid liquor.This preparation technology has significant limitation: on the one hand, this technique has been used a large amount of tert-butyl alcohols, and the toxicity of the tert-butyl alcohol has increased potential safety hazard than large of ethanol more; On the other hand, utilize the method for lyophilizing to remove organic solvent, energy resource consumption is large, and cost is higher, is not suitable for the production of medium-sized and small enterprises.
Patent US005213804A discloses the method that film dispersion method prepares liposome, in this patent phospholipid and cholesterol are dissolved in the chloroform, chloroform toxicity is large, increased potential safety hazard, to remove chloroform fully, cost is higher, and film dispersion method to prepare the liposome production lot little, limited industrialization.
Although spray drying method preparation technology is simple, the particle size distribution heterogeneity of the liposome of preparation, stability and the repeatability of technique are relatively poor, also are not suitable for preparing at present the Liposomal formulation of injection.
Alcohol injection is that phospholipid, cholesterol are dissolved in the ethanol as oil phase, be re-introduced into aqueous phase and form blank liposome, this method has following advantage: (1) has replaced conventional organic solvents, chloroform with ethanol, has increased safety coefficient, has guaranteed the quality of liposome product; (2) this method only needs oil phase is injected into the aqueous phase liposome that can be shaped with syringe needle, and is convenient and simple, is called undoubtedly the production method of the favor that is subjected to pharmaceuticals and drugmaker most.
Also there is a lot of restrictive factors strength by machinery as usual in industrial alcohol injection commonly used at present; oil phase is formed liposome according to the aqueous phase that certain volume ratio is injected into respective volume; because the restriction of water receiver volume; can not realize continuous production; difference between having increased batch has limited the large-scale production of liposome.
The granulate process of liposome, best with extrusion molding, but this method also has certain limitation:
(1) liposome of conventional 47mm is extruded instrument in vertical extrusion, and filter membrane very easily produces obstruction, even can have influence on the by the gross quality of liposome product, has seriously limited the large-scale production process of liposome.
(2) in order to enlarge the treating capacity of sample, generally all be to reach mass-produced purpose by increasing membrane area, need larger extrusion device but increase membrane area, not only production cost improves greatly, and the stability of extruding can not guarantee.
The aseptic process process of the Liposomal formulation of listing adopts disposable in-depth filtration film to carry out filtration sterilization according to the requirement great majority of SFDA at present.But because the particle size distribution heterogeneity of liposome, and the limitation of aseptic filtration membrane structure, general every 10min even shorter time need to be changed filter membrane one time, change filter membrane and not only improved production cost, the more important thing is, if in the asepticize processing procedure of a collection of liposome, gamble film, the asepticize of this batch product can not be guaranteed, so the method for filtration sterilization remains the bottleneck of restriction Liposomal formulation suitability for industrialized production, be China and even the common difficulty that faces of all researcher and R ﹠ D Enterprises in the world.The aseptic process system of improvement liposome lowers production cost, guarantees that having of asepticize production is to be solved.
Summary of the invention
The present invention discloses a kind of preparation technology of anthracene nucleus medicinal liposome injection, has overcome that existing production technology be difficult for to be amplified, cost is high, has been difficult to guarantee the repeatability of producing and the problem of serialization.
The preparation technology of anthracene nucleus medicinal liposome injection provided by the invention, its technical scheme is as follows:
(1) the microfluid focusing technology prepares liposome:
I phospholipid, cholesterol are dissolved in be mixed with phospholipid in the ethanol solution, the cholesterol final concentration is respectively the solution of 5.0～60.0g/L, 1.0～20.0g/L as oil phase;
II is dissolved in solution that the final concentration that is mixed with acid, sugar, buffer, anthracene nucleus medicament in the water for injection is respectively 1～100mM/L, 100～1000mM/L, 100～300mM/L, 1.0～10.0g/L as water with acid, sugar, buffer and anthracene nucleus medicament, and the pH of aqueous phase solution is below 4;
The water that III prepares more than inciting somebody to action process heat exchanger heats under the drive of peristaltic pump forms 30-50 ℃ liquid, enter three-way device and in three-way device, form two strands of equal-volumes and inject the current outflow, oil phase also forms the 30-50 temperature through heat exchanger heats and enters the four-way device under the drive of peristaltic pump simultaneously, mix with above-mentioned two strands of waters, such two strands of current clip one oil phase, in four-way, form " sandwich " structure, constantly extruding, collision, mixing are flowed out from the exit passageway of four-way, form liposome, enter in the fluid reservoir of liposome.
(2) liposome is extruded the instrument granulate:
The liposome solutions that obtains entered by inlet extrude instrument and (see Chinese utility model patent: 201220504642.1), part liposome passes through filter chamber, flow out from the liquid outlet of lower flange, another part liposome bottom horizontal flow sheet, flow out from the upper liquid outlet of upper flange plate, constantly wash away filter membrane by the principle of slipstream like this, avoid the obstruction of filter membrane, be to put in order under 20 ~ 800PSI 3 ~ 10 times at pressure, obtain the drug-loaded liposome that particle mean size is 70 ~ 110nm, and regulate pH to 6.0 ~ 7.0.
(3) secondary degerming, packing, preservation;
Drug-loaded liposome enters the slipstream that the 0.22um filter membrane is housed and thoroughly filters device under the drive of peristaltic pump, and the speed that peristaltic pump scalable drug-loaded liposome enters the filter device, valve on the filter device can be controlled the thoroughly speed of filter of drug-loaded liposome thoroughly, particle diameter is trapped greater than the product of 0.22um, get back in the initial fluid reservoir, to prevent that entering next in-depth filtration stage produces the situation that aseptic filter membrane stops up; Particle diameter can thoroughly be filtered the device from slipstream less than the drug-loaded liposome of 0.22um and thoroughly leach, and enters the deep layer sterile filtering device, finishes the degerming process, forms final product, thereby has guaranteed the serialization of aseptic filtration.
The envelop rate of the liposome that the present invention makes is high, the liposome of uniform particle diameter.
Good effect of the present invention is: adopting miniflow focusing technology, slipstream technology, molecular sieve liposome preparation technology, reduce the production cost of liposome, enlarge the production scale of liposome, is to think production process serialization, automatization.Adopt ethanol as the solvent of lipid mixtures, safety coefficient is higher, is fit to suitability for industrialized production.Adopt the circulation after improveing to extrude instrument, the extrusion serialization, penetrating rate increases, and has avoided gambling film phenomenon, has reduced production cost, has improved production efficiency.Adopt Fluid focus technology to prepare liposome, one step forming makes the production process serialization, reduces artificial disturbance, is conducive to aseptic assurance, and simple to operate, is fit to suitability for industrialized production.Adopt the pretreatment of slipstream microfiltration and vertical filtration sterilization, avoided the phenomenon of stifled film, production process serialization, scale.
The specific embodiment
Embodiment 1
The preparation of daunorubicin hydrochloride lipidosome injection comprises following steps:
(1) the microfluid focusing technology prepares liposome:
I is dissolved in hydrogenated soy phosphatidyl choline 40mg, cholesterol 10mg that to be mixed with phospholipid concentration in the 10mL ethanol solution be that 4.0g/L, cholesterol concentration are that the solution of 1.0g/L is as oil phase;
II is dissolved in solution that the final concentration that is mixed with hydrochloric acid, glucose, ammonium sulfate in the 200mL water for injection is respectively 10mM/L, 55mM/L, 250mM/L, 1.0g/L as water with hydrochloric acid, glucose, ammonium sulfate and daunorubicin hydrochloride, and the pH of aqueous phase solution is below 4;
The water that III prepares more than inciting somebody to action process heat exchanger heats under the drive of peristaltic pump forms 30 ℃ liquid, enter three-way device and in three-way device, form two strands of equal-volumes and inject the current outflow, oil phase also forms 30 ℃ through heat exchanger heats and enters the four-way device under the drive of peristaltic pump simultaneously, mix with above-mentioned two strands of waters, such two strands of current clip one oil phase, in four-way, form " sandwich " structure, constantly extruding, collision, mixing are flowed out from the exit passageway of four-way, form liposome, enter in the fluid reservoir of liposome.
(2) liposome is extruded the instrument granulate:
The liposome solutions that obtains entered by inlet extrude instrument and (see Chinese utility model patent: 201220504642.1), part liposome passes through filter chamber, flow out from the liquid outlet of lower flange, another part liposome bottom horizontal flow sheet from the upper liquid outlet outflow of upper flange plate, is constantly washed away filter membrane by the principle of slipstream like this, avoid the obstruction of filter membrane, be arrangement 6 times under the 600PSI at pressure, obtain the drug-loaded liposome that particle mean size is 103 ~ 107nm, and regulate pH to 6.5.
(3) secondary degerming, packing, preservation;
Drug-loaded liposome enters the slipstream that the 0.22um filter membrane is housed and thoroughly filters device under the drive of peristaltic pump, and the speed that peristaltic pump scalable drug-loaded liposome enters the filter device, valve on the filter device can be controlled the thoroughly speed of filter of drug-loaded liposome thoroughly, particle diameter is trapped greater than the product of 0.22um, get back in the initial fluid reservoir, to prevent that entering next in-depth filtration stage produces the situation that aseptic filter membrane stops up; Particle diameter can thoroughly be filtered the device from slipstream less than the product of 0.22um and thoroughly leach, and enters the deep layer sterile filtering device, finishes the degerming process, and packing obtains the daunorubicin hydrochloride liposome, stores under 4 ℃ of conditions.Five batches of every Index for examinations of product see Table 1
The every Index for examination catalog of five batches of daunorubicin hydrochloride liposomees of table 1
Embodiment 2
The preparation of hydrochloric doxorubicin liposome injection comprises following steps:
(1) the microfluid focusing technology prepares liposome:
I is dissolved in hydrogenated soy phosphatidyl choline 28mg, cholesterol 10mg that to be mixed with phospholipid concentration in the 5mL ethanol solution be that 5.6g/L, cholesterol concentration are that the solution of 2.0g/L is as oil phase;
II is dissolved in hydrochloric acid, maltose, citric acid and doxorubicin hydrochloride solution and is mixed with solution that the final concentration with hydrochloric acid, maltose, citric acid is respectively 10mM/L, 200mM/L, 250mM/L, 1.0g/L in the 100mL water for injection as water, and the pH of aqueous phase solution is below 4;
The water that III prepares more than inciting somebody to action process heat exchanger heats under the drive of peristaltic pump forms 50 ℃ liquid, enter three-way device and in three-way device, form two strands of equal-volumes and inject the current outflow, oil phase also forms 50 ℃ through heat exchanger heats and enters the four-way device under the drive of peristaltic pump simultaneously, mix with above-mentioned two strands of waters, such two strands of current clip one oil phase, in four-way, form " sandwich " structure, constantly extruding, collision, mixing are flowed out from the exit passageway of four-way, form liposome, enter in the fluid reservoir of liposome.
(2) liposome is extruded the instrument granulate:
The liposome solutions that obtains entered by inlet extrude instrument and (see Chinese utility model patent: 201220504642.1), part liposome passes through filter chamber, flow out from the liquid outlet of lower flange, another part liposome bottom horizontal flow sheet from the upper liquid outlet outflow of upper flange plate, is constantly washed away filter membrane by the principle of slipstream like this, avoid the obstruction of filter membrane, be arrangement 8 times under the 400PSI at pressure, obtain the drug-loaded liposome that particle mean size is 102 ~ 105nm, and regulate pH to 6.5.
(3) secondary degerming, packing, preservation;
Drug-loaded liposome enters the slipstream that the 0.22um filter membrane is housed and thoroughly filters device under the drive of peristaltic pump, and the speed that peristaltic pump scalable drug-loaded liposome enters the filter device, valve on the filter device can be controlled the thoroughly speed of filter of drug-loaded liposome thoroughly, particle diameter is trapped greater than the product of 0.22um, get back in the initial fluid reservoir, to prevent that entering next in-depth filtration stage produces the situation that aseptic filter membrane stops up; Particle diameter can thoroughly be filtered the device from slipstream less than the product of 0.22um and thoroughly leach, and enters the deep layer sterile filtering device, finishes the degerming process, and packing obtains the daunorubicin hydrochloride liposome, stores under 4 ℃ of conditions.Five batches of every Index for examinations of product see Table 2
The every Index for examination catalog of five batches of hydrochloric doxorubicin liposomes of table 2
As can be seen from Table 1, 2, the process stabilizing of liposome, envelop rate are 98 ~ 100%, about mean diameter 100nm.Prove that thus the stable processing technique of the anthracene nucleus medicinal liposome that this is novel can satisfy the requirement of liposome large-scale production.
The preparation of first's liposome
This part is described by thin film dispersion, ethanol injection (manual, nitrogen drives) and four kinds of methods of the present invention, compares four kinds of methods to the impact of the particle diameter of liposome.
Experimental example 1 relatively distinct methods prepares the liposome effect relatively
The experimental technique route
Get the 2g hydrogenated soy phosphatidyl choline, the cholesterol of 0.5g, respectively according to molten film dispersion method, manually alcohol injection, nitrogen is as driving force, alcohol injection, the present invention, and get the mensuration that each sample 1mL carries out particle diameter.Result such as following table 3
Liposome particle diameter and the distribution of the different preparation methoies of table 3
Conclusion: can find out that from above-mentioned experiment 1 adopt the liposome of the present invention's preparation, its particle diameter and PDI are better than front two kinds of methods, and avoid and overcome the deficiency of front two kinds of methods, the large-scale production that is used for liposome is significant.
The granulate of second portion liposome
This part is extruded two kinds of methods of instrument and is described by high pressure homogenization method, liposome being extruded the instrument method, two kinds of effects that methods are integrated the particle diameter of liposome relatively, and conventional liposome is extruded instrument and liposome of the present invention extrude instrument (see Chinese utility model patent: treating capacity 201220504642.1) compares.
Experimental example 2 liposomees of the present invention are extruded instrument and common contrast of extruding the treating capacity of instrument
The experimental technique route
According to 1 batch of liposome of experimental example 1 preparation, liposome is divided into two groups extrudes instrument (diameter 47mm) by liposome of the present invention respectively and conventional liposome is extruded instrument (diameter 47mm), initial operation pressure is 2MPa (290psi), measures the rate of outflow, operating pressure with the variation for the treatment of capacity.The results are shown in Table 4
Table 4 liposome of the present invention is extruded the contrast that instrument and conventional liposome are extruded instrument
Claims (1)
1. the preparation technology of an anthracene nucleus medicinal liposome injection comprises following steps:
(1) the microfluid focusing technology prepares liposome:
I phospholipid, cholesterol are dissolved in be mixed with phospholipid in the ethanol solution, the cholesterol final concentration is respectively the solution of 5.0～60.0g/L, 1.0～20.0g/L as oil phase;
II is dissolved in solution that the final concentration that is mixed with acid, sugar, buffer, anthracene nucleus medicament in the water for injection is respectively 1～100mM/L, 100～1000mM/L, 100～300mM/L, 1.0～10.0g/L as water with acid, sugar, buffer and anthracene nucleus medicament, and the pH of aqueous phase solution is below 4;
The water that III prepares more than inciting somebody to action process heat exchanger heats under the drive of peristaltic pump forms 30-50 ℃ liquid, enter three-way device and in three-way device, form two strands of equal-volumes and inject the current outflow, oil phase also forms the 30-50 temperature through heat exchanger heats and enters the four-way device under the drive of peristaltic pump simultaneously, mix with above-mentioned two strands of waters, two strands of waters clip one oil phase, constantly extruding, collision, mixing are flowed out from the exit passageway of four-way, form liposome, enter in the fluid reservoir of liposome;
(2) liposome is extruded the instrument granulate:
The liposome solutions that obtains entered by inlet extrude instrument, part liposome passes through filter chamber, flow out from the liquid outlet of lower flange, another part liposome bottom horizontal flow sheet from the upper liquid outlet outflow of upper flange plate, is constantly washed away filter membrane by the principle of slipstream, avoid the obstruction of filter membrane, be to put in order under 20 ~ 800PSI 3 ~ 10 times at pressure, obtain the drug-loaded liposome that particle mean size is 70 ~ 110nm, and regulate pH to 6.0 ~ 7.0;
(3) secondary degerming, packing, preservation;
Drug-loaded liposome enters the slipstream that the 0.22um filter membrane is housed and thoroughly filters device under the drive of peristaltic pump, and the speed that peristaltic pump scalable drug-loaded liposome enters the filter device, valve on the filter device can be controlled the thoroughly speed of filter of drug-loaded liposome thoroughly, particle diameter is trapped greater than the product of 0.22um, get back in the initial fluid reservoir, to prevent that entering next in-depth filtration stage produces the situation that aseptic filter membrane stops up; Particle diameter can thoroughly be filtered the device from slipstream less than the drug-loaded liposome of 0.22um and thoroughly leach, and enters the deep layer sterile filtering device, finishes the degerming process, forms final product.
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| CN114869851A (en) * | 2022-05-23 | 2022-08-09 | 浙江大学 | Preparation method of liposome for loading water-soluble drugs |
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